Bruton’s tyrosine kinase (BTK) inhibitors and mouse double minute 2 (MDM2) inhibitors are both targeted therapies used to treat patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). BTK inhibitors disrupt proliferation and release malignant B cells into circulating peripheral blood, while MDM2 inhibitors improve apoptosis of TP53 wild-type B cells.
Researchers of a phase 1b/2 study explored whether combining navtemadlin, an MDM2 inhibitor, with acalabrutinib, a BTK inhibitor, could improve treatment response in BTK inhibitor-naïve patients with relapsed or refractory (R/R) CLL or SLL. Results from the phase 1b portion of the study were presented at the European Hematology Association 2023 Hybrid Congress.
Lead author Dr. John Byrd reported navtemadlin plus acalabrutinib had acceptable safety and showed no dose-limiting toxicities during 3+3 dose escalation. The team also identified a recommended phase 2 dose of 240 mg and reported “encouraging preliminary activity” in the study’s cohort.
Combining Targeted Therapies in CLL, SLL
The primary end points of the phase 1b portion were recommended dose for phase 2 and the rates of complete remission (CR) and CR with incomplete count recovery (CRi). Secondary end points included overall response rate (ORR), duration of response, safety, and tolerability.
The study tested 3 doses of once-daily navtemadlin administered on days 1 to 7 of 28-day cycles in combination with continuous twice-daily acalabrutinib 100 mg. A 28-day lead-in of acalabrutinib monotherapy was tested but closed after the first 6 participants. As of February 2023, the phase 1b portion had enrolled 15 participants at 10 centers in 6 countries.
The cohort had a median age of 64 years, Eastern Cooperative Oncology Group scores of 0 or 1, a median of 1 prior line of therapy, and nearly half had unmutated immunoglobulin heavy chain disease. Additionally, 73% of the patients had Binet stage B/C disease, 27% had del11q, and none had del17p.
Among the 7 patients treated with the recommended phase 2 dose of 240 mg for 6 or more months, the ORR for partial response or better was 86%, and 2 patients achieved CR or CRi by week 32. Researchers added that all 6 patients who had initiated navtemadlin and acalabrutinib concurrently demonstrated minimal lymphocytosis and rapid reductions in absolute lymphocyte counts.
All participants reported treatment-emergent adverse events (TEAEs). The most common TEAEs of any grade and any cause were nausea (80%), diarrhea (60%), constipation (47%), fatigue (40%), vomiting (40%), headache (40%), thrombocytopenia (33%), cough (27%), and dizziness (27%). Grade 3 or 4 TEAEs occurred in 73% of participants, with the most common being diarrhea, thrombocytopenia, neutropenia (all 13%). No grade 5 events occurred.
Ultimately, the study’s authors concluded that navtemadlin plus acalabrutinib had an acceptable safety profile with promising preliminary activity in BTK inhibitor-naïve patients with relapsed or refractory CLL or SLL.
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